Added value of [18F]FDOPA PET to the management of high-grade glioma patients after their initial treatment: a prospective multicentre study.

BACKGROUND: Diagnostic value of 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine ([18F]FDOPA) PET in patients with suspected recurrent gliomas is recognised. We conducted a multicentre prospective study to assess its added value in the practical management of patients suspected of recurrence of high grade gliomas (HGG). METHODS: Patients with a proven HGG (WHO grade III and IV) were referred to the multidisciplinary neuro-oncology board (MNOB) during their follow-up after initial standard of care treatment and when MRI findings were not fully conclusive. Each case was discussed in 2 steps. For step 1, a diagnosis and a management proposal were made only based on the clinical and the MRI data. For step 2, the same process was repeated taking the [18F]FDOPA PET results into consideration. A level of confidence for the decisions was assigned to each step. Changes in diagnosis and management induced by [18F]FDOPA PET information were measured. When unchanged, the difference in the confidence of the decisions were assessed. The diagnostic performances of each step were measured. RESULTS: 107 patients underwent a total of 138 MNOB assessments. The proposed diagnosis changed between step 1 and step 2 in 37 cases (26.8%) and the proposed management changed in 31 cases (22.5%). When the management did not change, the confidence in the MNOB final decision was increased in 87 cases (81.3%). Step 1 had a sensitivity, specificity and accuracy of 83%, 58% and 66% and step 2, 86%, 64% and 71% respectively. CONCLUSION: [18F]FDOPA PET adds significant information for the follow-up of HGG patients in clinical practice. When MRI findings are not straightforward, it can change the management for more than 20% of the patients and increases the confidence level of the multidisciplinary board decisions.

Reduction in camera-specific variability in [(123)I]FP-CIT SPECT outcome measures by image reconstruction optimized for multisite settings: impact on age-dependence of the specific binding ratio in the ENC-DAT database of healthy controls.

PURPOSE: Quantitative estimates of dopamine transporter availability, determined with [(123)I]FP-CIT SPECT, depend on the SPECT equipment, including both hardware and (reconstruction) software, which limits their use in multicentre research and clinical routine. This study tested a dedicated reconstruction algorithm for its ability to reduce camera-specific intersubject variability in [(123)I]FP-CIT SPECT. The secondary aim was to evaluate binding in whole brain (excluding striatum) as a reference for quantitative analysis. METHODS: Of 73 healthy subjects from the European Normal Control Database of [(123)I]FP-CIT recruited at six centres, 70 aged between 20 and 82 years were included. SPECT images were reconstructed using the QSPECT software package which provides fully automated detection of the outer contour of the head, camera-specific correction for scatter and septal penetration by transmission-dependent convolution subtraction, iterative OSEM reconstruction including attenuation correction, and camera-specific "to kBq/ml" calibration. LINK and HERMES reconstruction were used for head-to-head comparison. The specific striatal [(123)I]FP-CIT binding ratio (SBR) was computed using the Southampton method with binding in the whole brain, occipital cortex or cerebellum as the reference. The correlation between SBR and age was used as the primary quality measure. RESULTS: The fraction of SBR variability explained by age was highest (1) with QSPECT, independently of the reference region, and (2) with whole brain as the reference, independently of the reconstruction algorithm. CONCLUSION: QSPECT reconstruction appears to be useful for reduction of camera-specific intersubject variability of [(123)I]FP-CIT SPECT in multisite and single-site multicamera settings. Whole brain excluding striatal binding as the reference provides more stable quantitative estimates than occipital or cerebellar binding.

European multicentre database of healthy controls for [123I]FP-CIT SPECT (ENC-DAT): age-related effects, gender differences and evaluation of different methods of analysis.

PURPOSE: Dopamine transporter (DAT) imaging with [(123)I]FP-CIT (DaTSCAN) is an established diagnostic tool in parkinsonism and dementia. Although qualitative assessment criteria are available, DAT quantification is important for research and for completion of a diagnostic evaluation. One critical aspect of quantification is the availability of normative data, considering possible age and gender effects on DAT availability. The aim of the European Normal Control Database of DaTSCAN (ENC-DAT) study was to generate a large database of [(123)I]FP-CIT SPECT scans in healthy controls. METHODS: SPECT data from 139 healthy controls (74 men, 65 women; age range 20-83 years, mean 53 years) acquired in 13 different centres were included. Images were reconstructed using the ordered-subset expectation-maximization algorithm without correction (NOACSC), with attenuation correction (AC), and with both attenuation and scatter correction using the triple-energy window method (ACSC). Region-of-interest analysis was performed using the BRASS software (caudate and putamen), and the Southampton method (striatum). The outcome measure was the specific binding ratio (SBR). RESULTS: A significant effect of age on SBR was found for all data. Gender had a significant effect on SBR in the caudate and putamen for the NOACSC and AC data, and only in the left caudate for the ACSC data (BRASS method). Significant effects of age and gender on striatal SBR were observed for all data analysed with the Southampton method. Overall, there was a significant age-related decline in SBR of between 4 % and 6.7 % per decade. CONCLUSION: This study provides a large database of [(123)I]FP-CIT SPECT scans in healthy controls across a wide age range and with balanced gender representation. Higher DAT availability was found in women than in men. An average age-related decline in DAT availability of 5.5 % per decade was found for both genders, in agreement with previous reports. The data collected in this study may serve as a reference database for nuclear medicine centres and for clinical trials using [(123)I]FP-CIT SPECT as the imaging marker.

Proposal for the standardisation of multi-centre trials in nuclear medicine imaging: prerequisites for a European 123I-FP-CIT SPECT database.

PURPOSE: Multi-centre trials are an important part of proving the efficacy of procedures, drugs and interventions. Imaging components in such trials are becoming increasingly common; however, without sufficient control measures the usefulness of these data can be compromised. This paper describes a framework for performing high-quality multi-centre trials with single photon emission computed tomography (SPECT), using a pan-European initiative to acquire a normal control dopamine transporter brain scan database as an example. METHODS: A framework to produce high-quality and consistent SPECT imaging data was based on three key areas: quality assurance, the imaging protocol and system characterisation. Quality assurance was important to ensure that the quality of the equipment and local techniques was good and consistently high; system characterisation helped understand and where possible match the performance of the systems involved, whereas the imaging protocol was designed to allow a degree of flexibility to best match the characteristics of each imaging device. RESULTS: A total of 24 cameras on 15 sites from 8 different manufacturers were evaluated for inclusion in our multi-centre initiative. All results matched the required level of specification and each had their performance characterised. Differences in performance were found between different system types and cameras of the same type. Imaging protocols for each site were modified to match their individual characteristics to produce comparable high-quality SPECT images. CONCLUSION: A framework has been designed to produce high-quality data for multi-centre SPECT studies. This framework has been successfully applied to a pan-European initiative to acquire a healthy control dopamine transporter image database.

Calibration of gamma camera systems for a multicentre European ¹²³I-FP-CIT SPECT normal database.

PURPOSE: A joint initiative of the European Association of Nuclear Medicine (EANM) Neuroimaging Committee and EANM Research Ltd. aimed to generate a European database of [(123)I]FP-CIT single photon emission computed tomography (SPECT) scans of healthy controls. This study describes the characterization and harmonization of the imaging equipment of the institutions involved. METHODS: (123)I SPECT images of a striatal phantom filled with striatal to background ratios between 10:1 and 1:1 were acquired on all the gamma cameras with absolute ratios measured from aliquots. The images were reconstructed by a core lab using ordered subset expectation maximization (OSEM) without corrections (NC), with attenuation correction only (AC) and additional scatter and septal penetration correction (ACSC) using the triple energy window method. A quantitative parameter, the simulated specific binding ratio (sSBR), was measured using the "Southampton" methodology that accounts for the partial volume effect and compared against the actual values obtained from the aliquots. Camera-specific recovery coefficients were derived from linear regression and the error of the measurements was evaluated using the coefficient of variation (COV). RESULTS: The relationship between measured and actual sSBRs was linear across all systems. Variability was observed between different manufacturers and, to a lesser extent, between cameras of the same type. The NC and AC measurements were found to underestimate systematically the actual sSBRs, while the ACSC measurements resulted in recovery coefficients close to 100% for all cameras (AC range 69-89%, ACSC range 87-116%). The COV improved from 46% (NC) to 32% (AC) and to 14% (ACSC) (p < 0.001). CONCLUSION: A satisfactory linear response was observed across all cameras. Quantitative measurements depend upon the characteristics of the SPECT systems and their calibration is a necessary prerequisite for data pooling. Together with accounting for partial volume, the correction for scatter and septal penetration is essential for accurate quantification.

Comparison of 3 γ-probes for simultaneous iodine-125-seed and technetium-99m breast cancer surgery: NEMA standard characterisation with extended processing.

PURPOSE: Iodine-125 (125I) seeds can be used as landmarks to locate non-palpable breast lesions instead of implanting metal wires. This relatively new technique requires a nuclear probe usually used for technetium-99m (99mTc) sentinel node detection. This study aimed to compare the performances of different probes and valid the feasibility of this technique, especially in the case of simultaneous 125I-seed and 99mTc breast cancer surgery. METHODS: Three probes with different features (SOE-3211, SOE-3214 and GammaSUP-II) were characterised according to the NEMA NU3-2004 standards for a 99mTc source and a 125I-seed. Several tests such as sensitivity, linearity or spatial resolution allowed an objective comparison of their performances. NEMA testing was extended to work on signals discrimination in case of simultaneous detection of two different sources (innovative figure of merit "Shift Index") and to assess the 99mTc scatter fraction, a useful parameter for the improvement of the probes in terms of detector materials and electronic system. RESULTS: Although the GammaSUP-II probe saturated at a lower activity (1.6 MBq at 10 mm depth), it allowed better sensitivity and spatial resolution at the different NEMA tests performed with the 99mTc source (7865 cps/MBq and 15 mm FWHM at 10 mm depth). With the 125I-seed, the GammaSUP-II was the most sensitive probe (3106 cps/MBq at 10 mm depth) and the SOE-3211 probe had the best spatial resolution (FWHM 20 mm at 10 mm depth). The SOE-3214 probe was more efficient on discriminating 125I from 99mTc in case of simultaneous detection. The SOE probes were more efficient concerning 99mTc scatter fraction assessments. The SOE-3211 probe, with overall polyvalent performances, seemed to be an interesting trade-off for detection of both 125I and 99mTc. CONCLUSION: The three probes showed heterogeneous performances but were all suitable for simultaneous 99mTc sentinel node and 125I-seed detection. This study provides an objective and innovative methodology to compare probes performances and then choose the best trade-off regarding their expected use.

Quantitative accuracy of dopaminergic neurotransmission imaging with (123)I SPECT.

UNLABELLED: 123I-Labeled radiotracers are suitable for in vivo imaging of the dopaminergic system by SPECT. However, precise measurement of striatal uptake is limited by scatter, attenuation, and the finite spatial resolution of the camera. We studied the quantitative accuracy that can be achieved with (123)I SPECT of the dopaminergic neurotransmission system. METHODS: Using a Monte Carlo simulation and brain phantom experiments, we studied the biases in brain and striatal absolute uptake estimates and in binding potential (BP) values for different processing schemes with corrections for attenuation, scatter, and the partial-volume effect. RESULTS: Without any correction, brain activity was underestimated by at least 65%, and absolute striatal activity measured in regions corresponding to the anatomic contours of the striata was underestimated by about 90%. With scatter and attenuation corrections only, estimated brain activity was accurate within 10%; however, striatal activity remained underestimated by about 50%, and BP values were underestimated by more than 50%. When combined with attenuation and scatter corrections, anatomically guided partial-volume effect correction (PVC) reduced the biases in striatal activity estimates and in BP values to about 10%. PVC reliability was affected by errors in registering SPECT with anatomic images, in segmenting anatomic images, and in estimating the spatial resolution. With registration errors of 1 voxel (2.1 x 2.1 x 3.6 mm(3)) in all directions and of 15 degrees around the axial direction, PVC still improved the accuracy of striatal activity and BP estimates compared with scatter and attenuation corrections alone, the errors being within 25%. A 50% overestimation of the striatal volume yielded an approximate 30% change in striatal activity estimates with respect to no overestimation but still provided striatal activity estimates that were more accurate than those obtained without PVC (average errors +/- 1 SD were -22.5% +/- 1.0% with PVC and -49.0% +/- 5.5% without PVC). A 2-mm error in the spatial resolution estimate changed the striatal activity and BP estimates by no more than 10%. CONCLUSION: Accurate estimates of striatal uptake and BP in (123)I brain SPECT are feasible with PVC, even with small errors in registering SPECT with anatomic data or in segmenting the striata.

Brain perfusion in Alzheimer's disease with and without apathy: a SPECT study with statistical parametric mapping analysis.

Alzheimer's disease (AD) is clinically characterized by cognitive symptoms that, in combination with behavioral disturbances, significantly interfere with activities of daily living. These behavioral disorders contribute to the clinical heterogeneity of the disease and probably express different pathophysiological processes. Apathy is one of the most frequent behavioral disorders in AD. The aim of this study was to evaluate brain perfusion of AD patients with and without apathy (as determined by the Neuropsychiatric Inventory) compared with that in healthy elderly subjects. A total of 15 AD patients without apathy (AD/NA; mean age 76.6) and 15 AD patients with apathy (AD/A; mean age 77.6) were studied. Brain perfusion was measured by 99mTc-labeled bicisate (ECD) single-photon emission tomography (ECD SPECT). The images of the two AD subgroups were compared by means of statistical parametric mapping (SPM 99) to corresponding images of 11 healthy elderly control subjects (obtained from the Society of Nuclear Medicine database). Compared with the healthy elderly subjects, the apathy-free AD subgroup had significantly lower perfusion of inferior temporal regions (left fusiform gyrus, left parahippocampal area) and occipital regions (left gyrus lingualis). The apathy subgroup had significantly decreased perfusion of the left anterior cingulate, the right inferior and medial gyrus frontalis, the left orbitofrontal gyrus and the right gyrus lingualis. The differences in the brain areas with reduced perfusion between the apathy-free subjects (mainly the posterior regions) and the apathetic subjects (mainly the anterior regions) indicate that behavioral disorders such as apathy participate in the heterogeneity of brain perfusion in AD.

Partial volume effect correction in SPECT for striatal uptake measurements in patients with neurodegenerative diseases: impact upon patient classification.

PURPOSE: In single-photon emission computed tomography (SPECT) of the dopaminergic system, measurements of striatal uptake are useful for diagnosis and patient follow-up but are strongly biased by the partial volume effect (PVE). We studied whether PVE correction might improve patient classification based on binding potential (BP) measurements. METHODS: Patients with a probable diagnosis of dementia with Lewy bodies (DLB, 10 patients) or Alzheimer's disease (AD, 13 patients) were studied by( 123)I-FP-CIT SPECT. SPECT images were reconstructed with and without PVE correction. Each patient SPECT scan was also simulated to obtain SPECT data whose characteristics were fully known. In addition, 17 SPECT scans were simulated with striatal uptake values mimicking pre-symptomatic cases of DLB. RESULTS: Without PVE correction, mean putamen BP values were 2.9+/-0.4 and 0.9+/-0.2 for AD and DLB patients respectively, while with PVE correction, they were 8.6+/-1.5 and 1.9+/-0.5 respectively. All patients were properly identified as having AD or DLB when considering mean putamen BP measured on their real or simulated SPECT scan, with and without PVE correction. All 30 simulations mimicking pre-symptomatic DLB and AD patients were accurately classified with PVE correction, but without PVE correction 15 mean putamen BP values were in a range where AD and DLB could not be distinguished. CONCLUSION: We conclude that putamen BP values measured without PVE correction can be used to differentiate probable DLB and AD due to the already severe reduction in dopamine transporter levels. PVE correction appeared useful for accurate differential diagnosis between AD and pre-symptomatic DLB.

Respiratory motion correction in emission tomography image reconstruction.

In Emission Tomography imaging, respiratory motion causes artifacts in lungs and cardiac reconstructed images, which lead to misinterpretations and imprecise diagnosis. Solutions like respiratory gating, correlated dynamic PET techniques, list-mode data based techniques and others have been tested with improvements over the spatial activity distribution in lungs lesions, but with the disadvantages of requiring additional instrumentation or discarding part of the projection data used for reconstruction. The objective of this study is to incorporate respiratory motion correction directly into the image reconstruction process, without any additional acquisition protocol consideration. To this end, we propose an extension to the Maximum Likelihood Expectation Maximization (MLEM) algorithm that includes a respiratory motion model, which takes into account the displacements and volume deformations produced by the respiratory motion during the data acquisition process. We present results from synthetic simulations incorporating real respiratory motion as well as from phantom and patient data.

99mTc-HMPAO and 99mTc-ECD perform differently in typically hypoperfused areas in Alzheimer's disease.

Technetium-99m hexamethylpropylene amine oxime (HMPAO) and (99m)Tc- N, N"-1,2-ethylene diylbis- l-cysteine diethyl ester dihydrochloride (ECD) yield significantly different images of cerebral perfusion owing to their particular pharmacokinetics. The aim of this study was to assess the topography, extension and statistical significance of these differences in Alzheimer's disease (AD). Sixty-four patients with mild to moderate AD were retrospectively selected by two European centres. Two series of patients, including 32 studied with (99m)Tc-HMPAO single-photon emission tomography (SPET) and 32 studied with (99m)Tc-ECD SPET, were matched for sex, age (+/-3 years) and severity of cognitive impairment as assessed by the Mini-Mental State Examination (MMSE) (+/-2 points), following a case-control procedure. SPET data were processed using SPM99 software (uncorrected height threshold: P=0.001). (99m)Tc-ECD SPET gave significantly higher uptake ratio values than (99m)Tc-HMPAO SPET in several symmetrical clusters, including the right and left occipital cuneus, the left occipital and parietal precuneus, and the left superior and middle temporal gyri. (99m)Tc-HMPAO SPET gave significantly higher uptake ratio values than ECD in two smaller clusters, including the hippocampus in both hemispheres. In AD, relative brain uptake of (99m)Tc-HMPAO and (99m)Tc-ECD is different in several brain regions, some of which are typically involved in AD, such as the precuneus and the hippocampus. These differences confirm the need for specific normal databases, but their impact on routine SPET reports in AD is not known and deserves an ad hoc investigation.

Exploración del sistema nervioso central: estado del arte en metodología / Exploring the central nervous system: methodological state of the art

El análisis de la práctica clínica actual demuestra un desfase entre los desarrollos metodológicos publicados y la utilización que de ellos se hace en la práctica clínica. Esta revisión propone una descripción de algunos desarrollos recientes que están próximos a una mayor difusión a propósito de tres indicaciones clásicas: el diagnóstico de la enfermedad de Alzheimer, la evaluación de la neurotransmisión dopaminérgica y el estudio de la epilepsia. En la enfermedad de Alzheimer los métodos de estandarización espacial y la comparación con una base de datos normativa son más útiles en la medida que el observador es menos experimentado y las aproximaciones "orientadas a la rutina" más simples que el SPM parecen prometedoras. La cuantificación es lo esencial del estudio de la neurotransmisión dopaminérgica. La medición de los potenciales de unión está considerablemente sesgado por la penetración septal, la atenuación, la difusión y el efecto de volumen parcial. Es el efecto de volumen parcial que introduce el mayor error. Su corrección es difícil debido a que pasa por un corregisto con imágenes de resonancia magnética. Los resultados de esa corrección son muy sensibles a la precisión de dicho corregistro. El estudio de la epilepsia por sustracción de los SPECT ictal e interictal ha demostrado su valor clínico. Es una operación de fusión de imágenes para la cual los métodos ya están bien definidos.